BASEL, Switzerland—Finding multiple therapeutic uses for a single compound (or, for that matter, a
single pathway that deals with multiple ailments) is of course what almost everyone hopes for in pharma and biotech research and development. Part of that is
the ability to find more markets and get more monetary value out of a therapeutic, of course, but it’s also about being able to achieve more with less
and getting cures to patients faster.

It’s safe to say that when it comes to neglected disease areas, finding a single
compound that can do more than attack one disease pushes the value of that “more with less” philosophy even higher.

As the team noted in the abstract of its paper “Proteasome inhibition for treatment of leishmaniasis, Chagas
disease and sleeping sickness,” published late last year in the journal Nature: “Chagas disease, leishmaniasis and sleeping sickness affect 20 million people worldwide and lead to more than 50,000 deaths
annually. The diseases are caused by infection with the kinetoplastid parasites Trypanosoma cruzi, Leishmania spp. and Trypanosoma
brucei spp., respectively. These parasites have similar biology and genomic sequence, suggesting that all three diseases could be cured with drugs that
modulate the activity of a conserved parasite target.”

“However, no such molecular targets or broad
spectrum drugs have been identified to date. Here we describe a selective inhibitor of the kinetoplastid proteasome (GNF6702) with unprecedented in-
vivo efficacy, which cleared parasites from mice in all three models of infection,” the authors continued. “GNF6702 inhibits the
kinetoplastid proteasome through a non-competitive mechanism, does not inhibit the mammalian proteasome or growth of mammalian cells, and is well-tolerated
in mice. Our data provide genetic and chemical validation of the parasite proteasome as a promising therapeutic target for treatment of kinetoplastid
infections, and underscore the possibility of developing a single class of drugs for these neglected diseases.”

As Elizabeth Dougherty wrote in a December 2016 article on the Novartis website about the research, “In large swaths of rural Latin America, an
insect called the kissing bug spreads a silent killer: Chagas disease. A bug bite can transfer a single-celled organism that takes up residence in several
different tissues. People can live with these unwanted guests without obvious symptoms for decades. Meanwhile, the parasites erode the walls of the heart and
intestines, which slowly lose function ... Similar unwanted guests cause African sleeping sickness and leishmaniasis, though these diseases have distinct and
more immediate symptoms.”

Because the microorganisms that cause these diseases are so closely related, the GNF
researchers decided to actively search for a compound that kills all three. As noted in the Nature article, they found one that was effective in
mice and, in so doing, found and exploited a common vulnerability among the parasites, potentially opening the door to developing a range of new therapies
that target this shared vulnerability.

Aside from the efficiency aspect of this research discovery attacking three
disease, it would be useful to patients individually, as current compounds are toxic to the patients as well as the parasites, whereas a targeted drug would
theoretically harm only the parasite

“We always thought that it might be possible to find a single class of
drugs that would be active against all three parasites,” says Frantisek Supek, lead author of the Nature article and a senior investigator at
GNF. “But it’s one thing to be aware of the possibility and another to actually find a molecule with the right properties.”

The researchers screened more than three million compounds against the parasites to see if any killed all three, a huge
process that fortunately took only two weeks per parasite using GNF’s robotic screening technology.

As
Dougherty noted in her story on the Novartis website: “They tested the compounds that were successful against the parasites in a separate set of
experiments on mammalian cells. The goal was to identify a narrower group of compounds that are effective against the parasites and that would not be toxic
to patients.

“One of the compounds showed particular promise, but according to Supek, it was just a starting
point. As a next step, a team of chemists led by Advait Nagle added and subtracted atoms to make the compound more like a drug. For instance, a potential
treatment must be potent so that patients don’t have to take it too often or for too long.”

Of course,
this is still preclinical data and while the compound eradicated infections in mice, there has as yet been no testing in humans.

These three diseases are most prevalent in South Asia, Africa and Latin America. Hot climates provide good breeding grounds
for the insects that transmit the parasites: the tsetse fly for African sleeping sickness, the sand fly for leishmaniasis, and the kissing bug for Chagas.
That said, the diseases don’t recognize borders. For example, there are approximately 300,000 people with Chagas disease infections living in the
United States and leishmaniasis has spread into Europe, with the most recent epidemic in Spain.

In addition to the
issue of potential toxicity, the current compounds for the disease are awkward or difficult to administer and/or store. As Dougherty writes, “Most must
be injected, often painfully, because the compounds sometimes crystallize in the syringe before the injection is complete. Some are difficult to mix and must
be kept cold. For Chagas, an oral treatment is available, but it must be taken for several months. Many people stop taking it because of its side
effects.”

Of course, as is often the case with such research, it isn’t just about the compound but
about gaining more understanding of the underlying biological mechanisms of the disease that allowed that compound to work as a therapeutic.

In this case, proteins were key in the work of the GNF researchers. The proteasome is a new and surprising therapeutic target
for Chagas disease, African sleeping sickness and leishmaniasis, according to Novartis, but a useful one: a slight difference between the parasite and the
mammalian proteasome means that it is possible to cripple the former without harming the latter.